P527: DISTINCTIVE CLONAL EVOLUTION PATTERN AND PROGNOSTIC SIGNIFICANCE OF THE CLONALITY OF KRAS MUTATIONS IN KMT2A-REARRANGED ACUTE MYELOID LEUKEMIA
Authors: Hidemasa Matsuo, Kenichi Yoshida, Yasuhito Nannya, Yuri Ito, Aina Inagami, Nana Ito, Shinju Iyoda, Shoji Saito, Yuhki Koga, Hiroshi Moritake, Kiminori Terui, Koji Kawaguchi, Yasuhiro Okamoto, Hideki Nakayama, Miyako Kanno, Moeko Hino, Yusuke Akane, Akiko Inoue, Akira Shimada, Hiroaki Goto, Hiroo Ueno, Junko Takita, Genki Yamato, Norio Shiba, Yasuhide Hayashi, Yuichi Shiraishi, Satoru Miyano, Nobutaka Kiyokawa, Daisuke Tomizawa, Takashi Taga, Akio Tawa, Seishi Ogawa, Souichi Adachi
Journal: HemaSphere (2023)

Background:KMT2A (MLL) rearrangements are among the most frequently occurring chromosomal aberrations in acute myeloid leukemia (AML). The driver mutations in KMT2A-rearranged AML have been identified. Our group showed that KRAS mutations (KRAS-MT) are independent adverse prognostic factors in KMT2A-rearranged AML (Blood Adv. 2020). However, most studies lack mutation data at relapse. Aims: We aimed to investigate the clonal evolution pattern and prognostic significance of the clonality of KRAS-MT in KMT2A-rearranged AML. Methods: Samples from pediatric patients with KMT2A-rearranged AML that were enrolled in the Japan Children's Cancer Group (JCCG) AML-05/AML-99 study included 62 diagnostic and 16 relapse samples and were analyzed for 338 genes by targeted sequencing. The data were analyzed with published data from 105 diagnostic and 11 relapse KMT2A-rearranged AML samples. As a control, mutation data were collected from 122 patients with non-KMT2A-rearranged AML at diagnosis and relapse. Results: Twenty-seven patients with KMT2A-rearranged AML and matched data at diagnosis and relapse, showed that mutations in signaling pathway genes (FLT3, KRAS, NRAS, PTPN11, CBL, and BRAF) were frequently detected in diagnostic samples (25 mutations/27 patients). At relapse, 21 out of 25 signaling pathway mutations (84.0%) and 7 out of 19 other pathway mutations (36.8%) were lost. The loss frequency of signaling pathway mutations was significantly higher than that of other pathway mutations (P=0.002). Mutations of transcription factor genes (WT1, SPI1, GATA2, IKZF1, and RUNX1) were predominantly acquired at relapse; 8 out of 9 mutations (88.9%) were detected at relapse. The percentage of patients with loss of signaling pathway mutations at relapse was 51.9% (14/27 patients), which was significantly higher than that in non-KMT2A-rearranged AML (29.5%, 36/122 patients) (P=0.04). Patients with KMT2A-rearranged AML with loss of signaling mutations at relapse (n=14) frequently acquired mutations of transcription factor genes/cell cycle gene (CCND3), compared with other patients (n=13) (50.0% vs. 7.7%, P=0.03). The other patients frequently acquired mutations of epigenetic regulator genes (SETD2, ASXL1, and BCOR) at relapse (30.8% vs. 0.0%, P=0.04). These patterns were not observed in the non-KMT2A-rearranged AML cohort. At diagnosis, 10 out of 27 patients (37.0%) harbored KRAS-MT that was lost at relapse in 9 out of 10 (90.0%) patients. Loss of KRAS-MT at relapse indicates that the mutations were in the subclones at diagnosis, and therefore, we examined the prognosis of 167 patients with KMT2A-rearranged AML according to the clonality of KRAS-MT at diagnosis. Patients with subclonal KRAS-MT (n=33) had adverse 5-year event-free-survival rates, compared with patients with wild-type KRAS (n=119) (wild-type vs. subclonal: 50.9% vs. 15.2%, P<0.0001) and patients with clonal KRAS-MT (n=15) (clonal vs. subclonal: 32.0% vs. 15.2%, P=0.22). RNA-sequencing analysis of diagnostic and relapse sample sets from four patients with KMT2A-rearranged AML including two with KRAS-MT loss at relapse was performed. Differentially expressed genes associated with relapse predominantly clustered in pathways related to immune response. Summary/Conclusion: Patients with KMT2A-rearranged AML have a distinctive clonal evolution pattern, compared with non-KMT2A-rearranged AML. Patients with subclonal KRAS-MT have adverse prognosis and deregulation of immune response pathways may be involved in relapse. Keywords: KMT2A, Acute myeloid leukemia, Relapse, Mutation